Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.